Nucleotides are indispensable precursors for the synthesis of both RNA and DNA. The biosynthesis of nucleotides is a vital process for all cells, since cells are unable to take up nucleotides from surrounding medium. One nucleotide, uridine monophosphate (UMP) can be synthesized from low molecular weight precursors via a de novo biosynthesis pathway. Alternatively, UMP can be synthesized by salvaging uracil in a series of steps known as the salvage pathway. Uridine kinase plays a role in catalyzing the conversion of uracil to UMP in the salvage pathway.
In the salvage pathway, first, uracil is converted to uridine, by reacting uracil and ribose-1-phosphate in the presence of uridine phorphorylase catalyst to form uridine and Pi. Next, the resulting uridine is converted to UMP by transferring Pi from adenosine triphosphate (ATP), via uridine kinase activity, to form UMP and adenosine diphosphate (ADP). Uridine kinase is the rate limiting enzyme in the salvage pathway for uridine or cytidine in mammalian cells (Ropp, P. A. et al. Archives of Biochem. and Biophysics (1998) 359(1):63-68). Cytidine is believed to be the only other physiological nucleoside to act as a substrate for uridine kinase to form CMP, but a variety of nucleoside triphosphates can act as phosphoryl donors. (Zubay, Geoffrey (1984) Biochemistry 712.)
In contrast to the salvage pathway, uridine kinase is not normally involved in the biosynthesis pathway of UMP. Such a biosynthesis pathway utilizes carbamoyl phosphate, which is synthesized from glutamine catalyzed by carbamoyl phosphate synthetase II (CPS-II). Carbamoyl phosphate is then converted to UMP via the intermediates orotic acid and orotate monophosphate (OMP), and can be further processed to make other nucleotides. UMP is involved in feedback regulation of CPS-II to attenuate orotic acid production. (King, Michael W. (1998) www.med.monash edu.au/biochem/theme/nucmetab.html).
Despite the availability of this de novo biosynthetic pathway, the mammalian liver provides a continuous supply of uridine to the circulatory system, suggesting that the salvage pathway is the major source for UMP and other pyrimidine nucleotides. Thus in disorders wherein a subject's nucleotide biosynthesis pathway is deficient and thus lacks the ability to synthesize UMP, treatment with uridine and/or uridine kinase leads to increased UMP production. Thus, uridine kinase may play a role in treating disorders relating to the nucleotide biosynthesis pathway.
The major function of pyrimidine nucleotide kinases, such as uridine kinase, is to maintain cellular balance between the level of pyrimidine nucleosides such as uridine and pyrimidine nucleoside monophosphates, in this case UMP. (King, Michael W. (1998) www.med.monash.edu.au/biochem/theme/nucmetab.html.) Uridine kinase activity is present in a variety of bacteria and animal cells, including tumors, and is especially high in cells of high growth rate. (Zubay, Geoffrey (1984) Biochemistry 712.) Uridine kinase has also been considered to be important in chemotherapy because uridine kinase has been shown to be required for the intracellular transformation of some pyrimidine nucleoside analogs to cytotoxic nucleotides. (Ropp, supra.)
In addition, uridine kinase activity has been found in rat brain. (Mascia, L. et al. Biochimica et Biophysica Acta-General Subjects (1999) 1472(1-2):93-98.) The rat homolog of uridine kinase has been found to be upregulated in tissues related to nerve regeneration, such as ventral horn tissue and the brain. (Yuh, I. et al. (1999) Biochemical and Biophysical Research Communications 266(1) 104-109.)